The identification of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) as the active compounds of marijuana (Cannabis sativa) prompted extensive research in medicinal chemistry and the development of numerous cannabinoid analogs, a class of diverse terpenophenols derived from Cannabis sativa and synthetic chemical compounds, that interact with cannabinoid receptors on cells and repress neurotransmitter release in the brain (Appendino G, Chianese G, Taglialatela-Scalfati O, Cannabinoids: occurrence and medicinal chemistry. Curr Med Chem 2011; 18: 1085-99; Massi P, Solinas M, Cinqina V, Parolaro D. Cannabidiol as potential anticancer drug. Br J Clin Pharmacol (2013) 75(2): 303-312).
The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive component of Cannabis sativa. Cannabidiol (CBD) is another major constituent of the plant. From Wikipedia, en.wikipedia.org/wiki/Tetrahydrocannabinol which was accessed May 25, 2015. All or any of these cannabinoids can be used in the present invention.
Synthetic cannabinoids encompass a variety of distinct chemical classes: the cannabinoids structurally related to THC, the cannabinoids not related to THC, such as (cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides, and eicosanoids related to the endocannabinoids. All or any of these cannabinoids can be used in the present invention.
Delta-9-tetrahydrocannabinol (dronabinol) is a naturally occurring compound and is the primary active ingredient in marijuana. Marijuana is dried hemp plant Cannabis sativa. The leaves and stems of the plant contain cannabinoid compounds (including dronabinol). Dronabinol has been approved by the Food and Drug Administration for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation of patients suffering from wasting syndrome. Synthetic dronabinol is a recognized pharmaceutically active ingredient (API), but natural botanical sources of Cannabis rather than synthetic THC are also known in the art. All or any of these cannabinoids can be used in the present invention.
Dronabinol is the international nonproprietary name for a pure isomer of THC, (−)-trans-Δ9-tetrahydrocannabinol, which is the main isomer, and the principal psychoactive constituent, found in Cannabis. Synthesized dronabinol is marketed as Marinol® (a registered trademark of Solvay Pharmaceuticals).
Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7. After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.
CBD does not have the clinically undesirable (but recreationally desirable) psychotropic effects, but is capable of inhibiting many effects of receptor ligands in the endocannabinoid system, which are responsible for the expression of THC's angiogenic and psychotogenic properties (Zuardi A W. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrm of action. Rev Bras Psiquiatr 30: 271-280). Despite its different pharmacological and behavioural effects, CBD shares many beneficial effects, including the capacity to act as an immunomodulator, with ‘classic’ psychocannabinoids (Kozela E, Lev N, et al. Cannabidiol has been shown to inhibit pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. (2011) Br J Pharmacol 163: 1507-1519).
Anti-Inflammatory Activities
Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory central nervous system (CNS) degenerative diseases. While clinical use of many cannabinoids is limited by their psychotropic effects, phytocannabinoids like CBD, which are devoid of psychoactive activity, are potentially safe and therapeutically effective alternatives for the alleviation of neuroinflammation and neurodegeneration (Kozela E, Lev N, et al. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. (2011) Br J Pharmacol 163: 1507-1519).
CBD exerts a wide range of anti-inflammatory properties and regulates cell cycle and function of various immune cells. These effects include suppression of humoral responses, such as release of cytokines, chemokines, growth factors, as well as suppression of immune cell proliferation, activation, maturation, migration, and antigen presentation (Mechoulam et al., Cannabidiol—recent advances. (2007) Chem Biodivers 4: 1678-1692).
Among the many types of neurodegenerative diseases in which inflammation is involved, multiple sclerosis (MS) is one of those clearly induced and driven by dysfunctional immune system activity. MS is a demyelinating disease which causes cytotoxic, degenerative processes, including inflammation, demyelination, oligodendrocyte cell death, and axonal degeneration. (Ribeiro R, Yu F, et al. This leads to neurological deficits and clinical symptoms of visual and sensory disturbances, motor weakness, tremor, ataxia, and progressive disability (Compston A, Coles A. Multiple sclerosis. (2008) Lancet 372: 1502-1517). There is currently no cure.
The endocannabinoid system has emerged as a promising therapeutic target for MS (Ribeiro R, Yu F, et al. Therapeutic potential of a novel cannabinoid agent C52 in the mouse model of experimental autoimmune encephalomyelitis. (2013) Neuroscience 254: 427-442). Several cannabinoids, including THC and CBD, exhibit anti-proliferative, anti-oxidative, and neuroprotective properties (Mechoulam R, Peters M, Murillo-Rodriguez E, et al. Cannabidiol—recent advances. (2007) Chem Biodivers 4: 1678-1692). Sativex® (GW Pharmaceuticals), the world's first pharmaceutical prescription medicine derived from the Cannabis plant, was launched in April 2005 for neuropathic pain relief in multiple sclerosis. It is a mixture of CBD and donabinol, and was most recently formulated as an oromucosal spray for the treatment of symptoms of spasticity associated with multiple sclerosis (G. W. Pharmaceuticals: Products and Pipeline. accessed at: www.gwpharm.com/products-pipeline/sativex on Mar. 5, 2017).
Most current MS therapies are directed against various immune cells to achieve immunosuppressive effects, but immunosuppression alone is insufficient for therapeutic effect, especially in late, secondary, progressive MS, where neurodegenerative processes become resistant to immunomodulation (Bennett J L, Stuve O. Update on inflammation neurodegeneration and immunoregulation in multiple sclerosis: therapeutic implications. Clin Neuropharmacol 32: 121-132).
It appears that in this unique aspect, the endocannabinoid system could provide a rescue mechanism, particularly for patients suffering from late-stage MS. Research indicates that THC-like cannabinoids possess ameliorating, neuroprotective activity in this respect, and that cannabinoid-mediated neuroprotection, rather than immunosuppression, is relevant for the recovery process at the later, remissive stages of MS (Croxford J L, Pryce G, et al. Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. J Neuroimmunol (2008) 193: 120-129; Maresz K. Pryce G et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. (2007) Nat Med 13: 492-497).
Cancer
Several studies have demonstrated that cannabinoids exert an inhibitory action on the proliferation of various cancer cell lines, and are able to slow down or arrest the growth of different models of tumour xenograft in experimental animals (Alexander A, Smith P F, Rosengren R J. Cannabinoids in the treatment of cancer. Cancer Lett 285: 6-12); Flygare J, Sander B. The endocannabinoid system in cancer-potential therapeutic target? Semin Cancer Biol 18: 176-189; Freimuth N, Ramer R, Hinz B, Antitumorogenic effects of cannabinoids beyond apoptosis. (2010) J Pharmacol Exp Ther 332: 336-344; Guindon J, Hohmann A G. The endocannabinoid system and cancer: therapeutic implication. (2011) Br J Pharmacol 163: 1447-1463). These data have attracted increasing interest for clinical exploitation of cannabinoid-based anti-cancer therapies.
Cannabinoids are currently used in cancer patients to palliate wasting, emesis, and pain that often accompany cancer (Massi P, Solinas M, Cinqina V, Parolaro D. Cannabidiol as potential anticancer drug. Br J Clin Pharmacol (2013) 75(2): 303-312). A shortcoming for these and forthcoming indications clearly lies in the psychoactive adverse effects of cannabinoids, resulting in increased interest in the non-psychoactive cannabinoid CBD in recent years (Ramer R, Merkord J, et al. Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1. (2010) Biochem Pharm 79: 955-966).
Meanwhile, a formulation including a 1:1 ratio of THC to CBD has been approved for pharmacotherapy of multiple sclerosis-related spasticity and pain in Canada (Wade D T, Makela P, et al. Do Cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? (2004) Mult Scler 10: 434-41). Further formulations and indications are needed; modulation of cancer cell invasion has recently emerged as a topic of increasing interest (McAllister S D, Christian R T, et al. Cannabidiol as a novel inhibitor of id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther 2007; 6:2921-7; Blazquez C, Salazar M, et al. Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. (2008) Cancer Res 68: 1945-52; Ramer R, Hinz B. Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. (2008) J Natl Cancer Inst 100: 59-69).
Several cannabinoids have been shown to exert anti-proliferative and pro-apoptotic effects in various cancer types (lung, glioma, thyroid, lymphoma, skin, pancreas, uterus, breast, prostate, and colorectal carcinoma) (D. Wade, P. Robson, H. House, et al., Clin. Rehabil. 17 (2003) 21e29; T. J. Nurmikko, M. G. Serpell, B. Hoggart, et al., Pain 133 (2007) 210e220; J. R. Johnson, M. Burnell-Nugent, D. Lossignol, et al., J. Pain Symptom Manage. 39 (2010) 167e1799; M. C. McCowen, M. E. Callender, J. F. Lawlis, Science 113 (1951) 202e203; F. Lantemier, D. Boutboul, J. Menotti, et al., Transpl. Infect. Dis. 11 (2009) 83e88; J. Breedt, J. Teras, J. Gardovskis, et al., Antimicrob. Agents Chemother. 49 (2005) 4658e4666). Other antitumourogenic mechanisms are emerging, showing their ability to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization (McGivem J G, Neuropsychiatr Dis. Treat. 3 (2007) 69-85).
The clinical use of THC and additional synthetic agonists is often limited by their unwanted psychoactive side effects, and for this reason, interest in non-psychoactive phytocannabinoids, such as CBD, has substantially increased in recent years. CBD does not have psychotropic activity and yet maintains very high potency. In 2006, CBD was used to selectively inhibit the growth of different breast tumour cell lines (MCF7, MDA-MB-231), while exhibiting lower potency in non-cancer cells (Ligresti A, Moriello A S, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V, Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 2006; 318: 1375-87).
CBD also possesses antitumoural properties in gliomas, tumours of glial origin characterized by a high morphological and genetic heterogeneity and considered one of the most devastating neoplasms, showing high proliferative rate, aggressive invasiveness and insensitivity to radio- and chemo-therapy (Massi P, Solinas M, Cinqina V, Parolaro D. Cannabidiol as potential anticancer drug. Br J Clin Pharmacol (2013) 75(2): 303-312). Research findings have also suggested a novel mechanism underlying the anti-invasive action of CBD on human lung cancer cells, and imply its use as a therapeutic option for the treatment of invasive cancers, as well as leukemia (S. Goodin, Am. J. Health-Syst Pharm. 65 (2008) S10eS15; F. Y. F. Lee, R. Borzilleri, C. R. Fairchild, et al., Cancer Chemother. Pharmacol. 63 (2008) 157e166; A. Conlin, M. Fornier, C. Hudis, et al., Eur. J. Cancer 44 (2008) 341e352; D. R. P. Guay, Consult Pharm. 24 (2009) 210e226; N. Slatkin, J. Thomas, A. G. Lipman, et al., J. Support Oncol. 7 (2009) 39e46; F. M. Reichle, P. F. Conzen, Curr. Opin. Invest. Drugs 9 (2008) 90e100; C. S. Yuan, Ann. Pharmacother. 41 (2007) 984e993; M. D. Kraft, Am. J. Health Syst. Pharm. 64 (2007) S13eS20; Novartis: Press release 30 Mar. 2009. Available at: www.novartis.com/accessed Mar. 5, 2017; D. L. Higgins, R. Chang, D. V. Debabov, et al., Antimicrob. Agents Chemother. 49 (2005) 1127e1134; J. K. Judice, J. L. Pace, Bioorg. Med. Chem. Lett. 13 (2003) 4165e4168; S. Avaleeson, J. L. Kuti, D. P. Nicolau, Expert Opin. Invest. Drugs 16 (2007) 347e357).
In addition to their anti-proliferative and pro-apoptotic actions, it has been shown that cannabinoids can affect other important processes in tumourigenesis, in particular, angiogenesis, or the formation of new blood vessels from pre-existing ones—an essential step in tumour growth, invasion, and metastasis and a major therapeutic target for cancer therapy (Solinas M, Massi P, Cantelmo A R, et al. Cannabidiol inhibits angiogenesis by multiple mechanisms. Brit J Pharmacol (2012) 167: 1218-31). Strategic approaches are needed that are aimed at the timely administration of natural, non-psychotropic cannabinoids (such as CBD) that are able to suppress pro-angiogenic factor production while binding with low affinity to cannabinoid receptors, thereby excluding psychotropic and immune or peripheral effects (Casanova M L, Blazquez C et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111: 43-50; Blazquez C, Gonzales Feria L, Alvarez L, et al. Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64: 5617-5623; Gertsch J, Pertwee R G, Di Marzo V, Phytocannabinoids beyond the Cannabis plant—do they exist? (2010) Br J Pharmacol 160: 523-29; Preet A, Ganju R K, Groopman J E. Delta-9-tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. (2008) Oncogene 27: 339-346; Russo E B. Taming THC: potential Cannabis synergy and phytocannabinoid-terpenoid entourage effects. (2011) Br J Pharmacol 163: 1344-1364).
Collectively, the non-psychoactive plant-derived cannabinoid CBD exhibits pro-apoptotic and anti-proliferative actions in different types of tumours and may also exert anti-migratory, anti-invasive, anti-metastatic, and perhaps anti-angiogenic properties. On this basis, evidence supports that CBD is a potent and selective inhibitor of cancer cell growth and spread (Massi P, Solinas M, Cinqina V, Parolaro D. Cannabidiol as potential anticancer drug. Br J Clin Pharmacol (2013) 75(2): 303-312). Considering its demonstrated clinical efficacy and safety in multiple sclerosis patients, the findings suggest that CBD is worthy of clinical consideration in an appropriate formulation for cancer therapy.
Mental Illness/Neuropathic Pain
Spinal cord injury and neuropathic pain are diseases in which alterations in the endocannabinoid system have been demonstrated, paving the way for new therapeutic strategies in which normal endocannabinoid system functionality is restored (Pacher P, Batkai S, Junos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006; 58: 389-462).
Sativex® was also approved for use in some countries as an adjunctive analgesic for severe pain in advanced cancer patients, reducing use of, and dependency on, opioid medications. It efficiently reduces pain in patients with advance cancer, and has been recommended by the FDA for direct entry into Phase III trials (Johnson J R, Burnell-Nugent M, Lossignol D, et al. J. Pain Symptom Manage. 39 (2010) 167-79).
Many studies present evidence that support the therapeutic potential of cannabidiol to mitigate the detrimental and psychotogenic effects of delta-9-tetrahydrocannabinol, mitigating its effects of acute induction of psychotic and anxiety systems (Bhattacharyya S, Morrison P D, Fusar-Poli P, et al. Opposite effects of THC and CBD on human brain function and psychopathology. Neuropsychopharmacol. 2009; 35: 764-774; Hagerty S L, Williams S L, Mittal V A, Hutchison K E, The Cannabis conundrum: Thinking outside the THC box. J Clin Pharmacol. 2015 August; 55(*): 839-41).
Where THC has anxiogenic effects, CBD reduces subjective anxiety, achieving clinically significant reductions in anxiety, cognitive impairment, and discomfort. (Fusar-Poli P, Crippa J A, Bhattacharyya S, et al. Distinct effects of delta-9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiat. 2009; 66: 95-105; Bergamaschi M M, Queiroz R H C, Chaga M H N, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacol. 2011; 36: 1219-1226.). Evidently, the effects of Cannabis are complex and arise from myriad cannabinoids; they are distinct from the artificially uniform effect of THC alone. The therapeutic effects of these cannabinoids can be harnessed most effectively through formulations which, as with the present invention, account for the complexity of cannabinoids and their interactions, and the mechanisms that underlie different effects of use in humans (i.e., cognitive effects versus anxiolytic or anxiogenic effects) (Hagerty S L, Williams S L, Mittal V A, Hutchison K E, The Cannabis conundrum: Thinking outside the THC box. J Clin Pharmacol. 2015 August; 55(*): 839-41).
Epilepsy
Epilepsy is a prevalent and devastating disorder of the CNS, which may be defined as a brain condition causing spontaneous recurrent seizures. These seizures are sometimes both progressively severe and accompanied by cognitive and behavioural comorbidities (Goldberg E M, Coulter D A. Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat. Rev. Neurosci. 14 (2013) 337-49).
Epileptogenesis (latency period) refers to a scantily understood cascade of events that generally transmute a non-epileptic brain into one that triggers spontaneous seizures; these events occur in a specific time window included between a brain-damaging insult such as stroke, infection, or genetic predisposition, and the onset of unprovoked and unpredictable seizures (Ibid.) During this period, a specific treatment may stop or modify the epileptogenic process and thereby positively influence the quality of life of an epileptogenic subject (White H S, Loscher W. Searching for the ideal epileptogenic agent in experimental models: single treatment versus combinatorial treatment strategies. (2014) Neurotherapeutics 11: 373-384; Citraro R, Leo A, et al. Antidepressants but not antipsychotics have antiepileptogenic effects with limited effects on comorbid depressive-like behavior in the wag/rij rat model of absence epilepsy. (2015) Br J Pharmacol 172: 3177-3188).
Currently, among the major unmet needs in the treatment of epilepsy there is the identification of disease-modifying drugs that can completely prevent epilepsy or slow its progression (Leo A, Russo E, Elia M. Cannabidiol and epilepsy: rationale and therapeutic potential. (2016) Pharma Res 107: 85-92). Unfortunately, many new antiepileptic drugs (AEDs) as well as older AEDs present solely symptomatic features, and do not possess antiepileptogenic or disease modifying features, and show several negative side effects influencing quality of life as much as seizures (Kwan P, Brodie M J, Refractory epilepsy: mechanisms and solutions. (2006) Expert Rev Neurother 6: 397-406; Perucca P, Gilliam F G, Adverse effects of antiepileptic drugs, (2012) Lancet Neurol 11: 792-802).
Emphasis has been placed on phytocannabinoids, which has demonstrated clinically significant antiseizure effects in clinical trials (Reddy D S, Golub V, The pharmacological basis of Cannabis therapy for epilepsy, J Pharmacol Exp Ther (2016) 45-55). Anecdotal reports indicate mixed findings for seizure prevalence subsequent to administration of THC, however, where a greater prevalence of grand mal seizures may be observed subsequent to consumption in previously seizure-free patients (Ramsey H H, Davis J P. Anti-epileptic action of marijuana-active substances, Fed Proc 8 (1949), 67; Consroe P F, Wood G C, Buchsbaum H. Anticonvulsant nature of marihuana smoking. JAMA (1975) 234: 306-307; Ellison J M, Gelwan E, Ogletree J. Complex partial seizure symptoms affected by marijuana abuse. J Clin. Psychiatry (1990) 51: 439-440; Keeler M H, Reifler C B. Grand mal convulsions subsequent to marijuana use. Case report. Dis. Nerv. Syst. (1967) 28: 474-75).
Rather than a “blunt instrument” approach to administration of medical Cannabis, these studies of epileptic sujects suggest the need for highly nuanced formulations which account for the varying properties of each substituent cannaboid(s), and account for the desired pharmacokinetics of each based on the desired therapeutic effect sought to be achieved in the patient. The present invention affords such a nuanced mechanism of action, over and above the existing art in this field.
Studies have also suggested that desired therapeutic effects can be achieved via administration of pure CBD in twice-daily dosages in paediatric patients, resulting in seizure reduction ranging from total seizure freedom to reductions of 25-80%, and the absence of deleterious side effects (Saade D, Joshi C. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: A case report. Pediatr. Neurol. 52 (2015) 544-47; Porter B E, Jacobson C. Report of a parent survey of cannabidiol-enriched Cannabis use in pediatric-resistant epilepsy. Epilepsy Behav (2013) 29: 574-77). The present formulation is capable of achieving sustained therapeutic effect in a single dose, negating the cost and necessity of multiple dosages, and improving adherence, particularly in paediatric, elderly, and severely epileptic populations, where adherence is difficult and consequences are severe. As such, the present invention offers significant advantages over and above existing antiepileptic drugs (AEDs), accompanied by a superior pharmacokinetic, pharmacodynamic, and side effects profile. With demonstrated effects on cognitive performance and mood disorders, the present invention possesses the additive value of simultaneously managing psychiatric comorbidities associated with epilepsy, which are often more harmful to patients than seizures themselves (Dos Santos R G, Hallak J E, et al. Phytocannabinoids and epilepsy. J Clin Pharm Ther (2015) 40: 135-43; Scuederi C, Filippis D D, et al. Cannabidiol in medicine: a review of its therapeutic potential in cns disorders. Phytother. Res. (2009) 23: 597-602). The present invention, with its established safety profile, ease of use, and reliable evidence base of therapeutic efficacy will be of additional value for drug-resistant epilepsies which are non-responsive to conventional AEDs (Leo A, Russo E, Elia M. Cannabidiol and epilepsy: rationale and therapeutic potential. (2016) Pharma Res 107: 85-92).
Mood Disorders
High CBD intake relative to THC has been associated with lower scores on the positive dimensions of the CAPE (Community Assessment of Psychic Experiences) Scale, inhibition of psychotic symptoms, and reduced deficiencies in episodic memory (Englund A, Morrison P, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Pharmacol (2013) 27(1): 19-27). The present formulation presents the advantage of an intentional dosage of synthetic or natural preparations with ideal pharmacology, to the exclusion of other cannabinoids and their respective pharmacokinetic and pharmacodynamics influences. The “protective effects” afforded by extended or sustained release formulations can be harnessed by virtue of the present invention, along with the desired therapeutic effects of cannabidiols like CBD, either alone or in concert with therapeutically effective amounts of other cannabinoids. (Englund A, Morrison P, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Pharmacol (2013) 27(1): 19-27).
Research has also indicated that the endocannabinoid system is intricately involved in the pathophysiology of depression, with CB1 receptors widely distributed in brain areas related to affective disorders, where expression is otherwise regulated by anti-depressants (Devane W A, Dysarz F A, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol (1988) 34: 605-613; Hill M N, Gorzalka B B. Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? Behav Pharmacol (2005) 16: 333-352; Hill M N, Carrier E J, et al. Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment. J Neurochem (2008) 106: 2322-36).
Administration of CBD achieves characteristic effects of induced anti-psychotic and anxiolytic activity in subjects, and also attenuates the development of stress-induced behavioural consequences, raising the possibility that CBD could be useful for treating psychiatric disorders thought to involve impairment of stress-coping mechanisms, such as depression (Guimaraes F S, Chiaretti™, et al. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (1990) 100: 558-559; Resstel L B, Joca S R, et al. Effects of cannabidiol and diazepam on behavioural and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res (2006) 172(2): 294-98; Resstel L B, Tavares R F, et al. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol (2009) 156(1): 181-88; Zuardi A W, Shirakawa I, et al. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (1982) 76: 245-50).
Studies indicate that CBD has a favorable profile in a model predictive of antidepressant-like activity in comparison to prototype antidepressants, but that such effects are only attainable at precise dosages, with smaller or higher doses producing no effect (Porsolt R D, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatment. Nature (1977) 266: 730-32; Zanelati T V, Biojone C, et al. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol (2010) 159: 122-28). The present invention has a formulation which is capable of administering said dosage in accordance with the most clinically appropriate pharmacokinetic and pharmacodynamic profile in order to achieve desired therapeutic effects in a patient presenting with a specific pathophysiology, such as major depressive disorder.
Sleep
Delta-9-tetrahydrocannabiniol (THC) increases sleep (Pivik, R. T., Zarcone, V., Dement, W. C. and Hollister, L. E. (1972) D-9-tetrahydrocannabinol and synhexl: effects on human sleep patterns. Clin. Pharmacol. Ther. 13 (3), 426-435; Feinberg, I., Jones, R., Walker, J. M., Cavness, C. and March, J. (1975) Effects of high dosage D-9-tetrahydrocannabinol on sleep patterns in man. Clin. Pharmacol. Ther. 17 (4), 458-466; Feinberg, I., Jones, R., Walker, J., Cavness, C. and Floyd, T. 1n (1976) Effects of marijuana extract and tetrahydrocannabinol on electroencephalographic sleep patterns. Clin. Pharmacol. Ther. 19 (6), 782-794). The chemistry of CBD has been examined, and its central nervous system (CNS) pharmacological properties, including its anticonvulsant, anxiolytic, and sedative effects, have been documented (Chesher, G. B., Jackson, D. M. and Malor, R. M. (1975) Interaction of D9-tetrahydrocannabinol and cannabidiol with phenobarbitone in protecting mice from electrically induced convulsions. J. Pharm. Pharmacol. 27 (8), 608-609; Pickens, J. T. (1981) Sedative activity of Cannabis in relation to its D0-trans-tetrahydrocannabinol and cannabidiol content. Br. J. Pharmacol. 72 (4), 649-656; Russo, E. and Guy, G. W. (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med. Hypotheses 66 (2), 234-246).
In studies, it has been shown that CBD improves sleep in individuals suffering from insomnia (Carlini E A, Cunha J M, Hypnotic and antiepileptic effects of cannabidiol. J. Clin. Pharmacol. 21 (suppl 8-9), 417S-427S). It has been successfully employed to block anxiety-induced REM sleep alteration via its anxiolytic effects (Hsiao Y., Yi P, et al. Effect of cannabidiol on sleep disruption induced by the repeated combination tests consisting of open field and elevated plus-maze in rats. Neuropharmacol. (2012) 62: 373-84). Other studies have exhibited clinically significant improvements in sleep in subjects suffering from post-traumatic stress-related insomnia, even when subjects received no pharmaceutical medications to treat sleep disorders aside from cannabidiol oil (Shannon S., Effectiveness of cannabidiol oil for pediatric anxiety and insomnia as part of posttraumatic stress disorder: a case report. Perm J. (2016) 20(4): 16-005). In other studies, the systemic acute administration of CBD appears to increase total sleep time in subjects, in addition to increasing sleep latency in the light period of the day of administration (Chagas M., Crippa J., et al. Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats. J. Psychopharmacol. (2013) 27(3): 312-16).
Addiction and the Endocannabinoid System
Drug addiction is a chronic, relapsing disease characterized by the compulsion to seek and take a drug, loss of control in limiting intake and emergence of negative emotional states when access to the drug is prevented (Koob and Le Moal, Drug abuse: hedonic homeostatic dysregulation (1997) Science 278: 52-58.) It is a chronic disorder involving persistent changes in the central nervous system.
Prototypical examples of those changes include tolerance, dependence, and/or sensitization after repeated drug exposure with corresponding neurochemical changes in the brain (Chao and Nestler, Molecular neurobiology of drug addiction (2004) Annu Rev Med. 55:113-132; Nestler, Molecular mechanisms of drug addiction (2004) Neuropharm. 47:24-32; Ron and Jurd, The ‘ups and downs’ of signaling cascades in addiction (2005) Sci STKE 309:re 14). It is these neuropharmacological and neuroadaptive mechanisms that mediate the transition from occasional, controlled drug use to the loss of behavioral control over drug-seeking and drug-taking that defines addiction.
These emotional, cognitive and behavioral effects are commonly linked to a neurobiological subtract. The endocannabinoid system is strongly implicated in these neuroadaptations, which are induced through repeated exposure to drugs of abuse (Fattore et al. Endocannabinoid system and opioid addiction: behavioral aspects (2005) Pharmacol Biochem Behav 81: 343-359). Such findings include the main legal and illegal drugs used in developed countries: nicotine, alcohol, cannabis, cocaine and opioids (Arnold, The role of endocannabinoid transmission in cocaine addiction (2005) Pharmacol Biochem Behav 81: 396-406; Colombo et al. Endocannabinoid system and alcohol addiction: pharmacological studies (2005) Pharmacol Biochem Behav 81: 369-380; Lopez-Moreno et al., Functional interactions between endogenous cannabinoid and opioid systems: focus on alcohol, genetics and drug-addicted behaviors (2010) Curr Drug Targets 11: 406-428; Maldonado and Berrendero, Endogenous cannabinoid and opioid systems and their role in nicotine addiction (2010) Curr Drug Targets 11: 440-449; Maldonado et al., Involvement of the endocannabinoid system in drug addiction (2006) Trends Neurosci 29: 225-232; Piomelli, The endogenous cannabinoid system and the treatment of marijuana dependence (2004) Neuropharmacology 47(Suppl 1): 359-367).
The complexity of the endocannabinoid system is reflected by its implication in many different cognitive and physiological processes. It participates in the regulation and modulation of learning and memory, food intake, nociception, motor coordination, reward processes, emotional control, and various cardiovascular and immunological processes (Ameri, The effects of cannabinoids on the brain (1999) Prog Neurobiol 58: 315-348). The participation of the endocannabinoid system in most of these functional psycho-psychological processes is explained by its strong connection to the dopaminergic system, mainly through the basal ganglia and corticolimbic brain structures (Freund et al., Differences in norepinephrine clearance cerebellar slices from low-alcohol-sensitive and high-alcohol sensitive rats (2003) Alcohol 30: 9-18).
The main excitatory and inhibitory systems of the mammalian central nervous system are under the influence of the endocannabinoid system. In the addicted individual, the imbalance in glutamatergic neurotransmission is common. It is also known that a dysregulation of excitatory signaling could lead to the relapse of drug use and cravings, supporting the notion of addictive behavior as a chronic disorder (Dackis and O'Brien, Glutamatergic agents for cocaine dependence (2003) Ann N Y Acad Sci 1003:328-345). Therefore, it is easy to understand the importance of the endocannabinoid system in the phenomenon of addiction, especially when its neuromodulation is compromised, for example, by an altered performance of receptors and cellular signaling of cannabinoid CB1 receptors (Lopez-Moreno, et al. The pharmacology of the endocannabinoid system: functional and structural interactions with other neurotransmitter systems and their repercussions in behavioral addiction (2008) Addiction Biol. 13: 160-187). The endocannabinoid system is the major player and a neurobiological mechanism underlying drug reward (Onaivi, An endocannabinoid hypothesis of drug reward and addiction (2008) 1139: 412-21). The endocannabinoid system is a modulator of dopaminergic activity in the basal ganglia, elucidating its participation in the primary rewarding effects of alcohol, opioids, nicotine, cocaine, amphetamine, cannabinoids, and benzodiazepines through the release of endocannabinoids that act as retrograde messengers to inhibit classical transmitters, including dopamine, serotonin, GABA, glutamate, acetylcholine, and norepinephrine (Onaivi, An endocannabinoid hypothesis of drug reward and addiction (2008) 1139: 412-21). The endocannabinoid system is further involved in the common mechanisms underlying relapse to drug-seeking behavior by mediating the motivational effects of drug-related environmental stimuli and drug re-exposure (Maldonado et al., Involvement of the endocannabinoid system in drug addiction (2006) Trends Neurosci 29: 225-232.) The endocannabinoid system triggers or prevents reinstatement of drug-seeking behavior (Fattore et al., An endocannabinoid mechanism in relapse to drug seeking: a review of animal studies and clinical perspectives (2007) Brain Res Rev 53: 1-16).
The perturbation of the endocannabinoid system by drugs of abuse can be ameliorated by restoring the perturbed system using cannabinoid receptor ligands. Cannabinoid receptor antagonists are useful in the reduction of drug use, in smoking cessation, and reduction in alcohol consumption, and rimonabant has been demonstrated to have antagonistic activity against disruption of cognition or reward-enhancing properties of morphine, amphetamine, cocaine, (Poncelet, Blockade of CB1 receptors by 141716 selectively antagonizes drug-induced reinstatement of exploratory behavior in gerbils (1999) Psychopharmacology 144: 144-50) ethanol, and diazepam. The blockade of the behavioral aversions by cannabinoid anatagonists after chronic administration of alcohol, cocaine, and diazepam is in agreement with data obtained during cannabinoid-induced alterations in brain dispositions of drugs of abuse that correlated with behavioral alterations in mice (Reid and Bornheim, Cannabinoid-induced alterations in brain disposition of drugs of abuse (2001). Biochem. Pharmacol. 61: 1357-1367).
As the mesolimbic dopaminergic system is implicated in the reinforcing properties of most drugs of abuse, the endocannabinoid system is a therapeutic target for individuals addicted to drugs. Mice treated with CB1 antagonists (i.e. SR141716) showed a significant reduction in self-administered alcohol consumption (Colombo et al., Suppressing effect of the cannabinoid CB1 receptor antagonist, SR 141716, on alcohol's motivational properties in alcohol-preferring rats (2004) Eur J Pharmacol 498: 119-123.), cocaine-related locomotor activity (Gerdeman et al., Context-specific reversal of cocaine sensitization by the CB1 cannabinoid receptor antagonist rimonabant (2008) Neuropsychopharmacology 33: 2747-2759.), and a reduction in the reward effects of nicotine (Cohen et al., SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats (2002) Behav Pharmacol 13: 451-463.)
The inhibition of FAAH (e.g. by URB597) causes a reduction of nicotine-induced dopamine activity in the nucleus accumbens, leading to a reduction in nicotine-induced reinstatement of nicotine seeking (Forget et al., Inhibition of fatty acid amide hydrolase reduces reinstatement of nicotine seeking but not break point for nicotine self-administration—comparison with CB(1) receptor blockade (2009) Psychopharmacology (Berl) 205: 613-624.)
Thus, the endocannabinoid physiological control system is a directly important natural regulatory mechanism for reward in the brain, and also contributes to reduction in aversive consequences of abused substances, such that manipulating the endocannabinoid system can be exploited in order to treat alcohol and drug dependency, and to reduce the behavioral consequences associated with withdrawal (Onaivi, An endocannabinoid hypothesis of drug reward and addiction (2008) 1139: 412-21).
Opioid Addiction
Abuse of heroin and prescription opioids have long constituted a significant burden to society both through the direct and indirect consequences of illicit opioid use. Since the mid-1990's heroin use has experienced a resurgence, particularly among younger populations. In 2004, an estimated 3.7 million people in the United States had reported using heroin at some point in their lifetime according to data collected by the National Institute on Drug Abuse. The 2008 National Survey on Drug Use and Health determined that the number of heroin users over the age of 12 in the United States had increased dramatically from 153,000 in 2007 to 213,000 in 2008.
The high abuse liability of heroin was demonstrated in a 2004 study of drug use, which found that 67% of those that used heroin also met the criteria for abuse or dependence, a statistic markedly higher than that for other drugs of abuse such as cocaine, marijuana, or sedatives (OAS).
Heroin use, while extremely problematic, is restricted to a small percentage of the population. However, non-medical use of prescription opioids is now becoming more prevalent with rates of use rapidly increasing. The misuse or abuse of prescription drugs occurs when a person takes a prescription drug that was not prescribed or taken in one dose or for reasons other than those prescribed. Abuse of prescription drugs can produce serious health effects, including addiction. The classes of prescription drugs that are commonly abused include include oral narcotics such as hydrocodone (Vicodin), oxycodone (OxyContin), propoxyphene (Darvon), hydromorphone (Dilaudid), meperidine (Demerol) and diphenoxylate (Lomotil), and their non-medical use has increased dramatically in recent years. For example, in 1990, the number of individuals initiating abuse of prescription opioids was 573,000. By the year 2000, the number had risen to over 2.5 million according to the National Institutes of Health. In 2009, for the first time, the number of individuals initiating prescription opioid use nearly equaled that of marijuana; a previously unprecedented and alarming finding. Concurrently, emergency department visits due to complications from non-medical use of hydrocodone and oxycodone rose by 170% and 450% respectively from 1994 to 2002. Furthermore, opioid-related deaths rose by more than 300% between 1999 and 2006 (OAS, 2009).
Similarly, withdrawal from opiates, such as heroin or oral narcotics, is characterized by a host of aversive physical and emotional symptoms. High rates of relapse and limited treatment success rates for opiate addiction have prompted a search for new approaches. Research over the past decade has shed light on the influence of endocannabinoids on the opioid system. Evidence from both animal and clinical studies show an interaction between these two systems, and targeting the EC system as provided by the instant invention provides a novel intervention strategy for managing opiate dependence and withdrawal.
Opioids, such as heroin and morphine, exert their physiological and behavioral effects through specific interactions with opioid receptors (Kieffer, Opioids: first lessons from knockout mice (1999) Trends Pharmacol Sci 20:19-26; Matthes et al., Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene (1996). Nature 383:819-823.) CB1 and μ-receptors are similarly expressed in many brain areas involved in reward processes (Herkenham et al., Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study (1991). J Neurosci 11:563-583; Matsuda et al., Localization of cannabinoid receptor mRNA in rat brain (1993). J Comp Neurol 327(4), 535-550.) These receptors share common signaling cascades (Howlett, (2002). The cannabinoid receptors. Prostaglandins Other Lipid Mediat 68-69, 619-631.) There is a functional interaction between the endogenous cannabinoid and opioid systems (Manzanares et al., Pharmacological and biochemical interactions between opioids and cannabinoids (1999). Trends Pharmacol Sci 20(7), 287-294.)
Studies have demonstrated that under certain circumstances, cannabis use can be associated with positive treatment prognosis among opioid-dependent cohorts. For example, Epstein and Preston found that cannabis abuse and dependence were predictive of decreased heroin and cocaine use during treatment (Epstein and Preston, Does cannabis use predict poor outcome for heroin-dependent patients on maintenance treatment? Past findings and more evidence against (2003) Addiction 98:269-279).
Intermittent use of cannabis was associated with a lower percentage of positive opioid relapses and improved medication compliance on naltrexone therapy (Church et al., Concurrent substance use and outcome in combined behavioral and naltrexone therapy for opiate dependence (2001) Am J Drug Alcohol Abuse 27:441-452). Similarly, associations of intermittent or occasional cannabis use with improved retention in treatment for opioid dependence have also been reported (Ellner, (1977) Marijuana use by heroin abusers as a factor in program retention. J Consult Clin Psychol 45:709-710). Among opioid-dependent individuals undergoing naltrexone therapy, intermittent cannabis users (with 1-80% of UDS positive for cannabis) fared better than cannabis abstinent or consistent cannabis users in terms of treatment retention and medication compliance (Raby et al., Intermittent marijuana use is associated with improved retention in naltrexone treatment for opiate-dependence (2009) Am J Addict 18:301-308.)
CB1 receptors influence the rewarding effects of opiates. CB1 receptor anatagonists block the development of morphine-induced conditioned place preference in rats and mice (Chaperon et al., Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats (1998). Psychopharmacology (Berl) 135(4), 324-332.), and mice lacking CB1 receptors display reduced morphine-induced CPP (Rice et al., Conditioned place preference to morphine in cannabinoid CB1 receptor knockout mice (2002). Brain Res 945(1), 135-138.) CB1 receptor knockout mice do not acquire heroin self-administration. SR141716A dose-dependently reduces heroin self-administration in rats (Navarro et al., Functional interaction between opioid and cannabinoid receptors in drug self-administration (2001, J Neurosci 21(14), 5344-5350).
Thus CB1 antagonists, such as those provided in the present invention, can be used to selectively treat conditioned place preference and prevent the genesis of opioid dependency (Manzanedo et al., Cannabinoid agonist-induced sensitisation to morphine place preference in mice (2004).
While medical cannabis is used widely in conjunction with opioids, as well as in conjunction with the administration of opiate-based narcotics for the treatment of chronic and acute pain, there is a need for a more nuanced dosage administration that will precisely administer the cannabinoids that will alleviate dependency, rather than cultivate it.
Stimulant Addiction
Recent evidence also supports the involvement of the endocannabinoid system in the neurobiological processes related to stimulant addiction. Addiction to psychostimulants such as cocaine, amphetamine, and its derivatives (i.e., methamphetamine, N-methyl-3,4-methylenedioxymethamphetamine (MDMA)) is a significant public health problem affecting many aspects of social and economic life, with between 16 and 51 millions substance users worldwide (Oliere et al., Modulation of the endocannabinoid system: vulnerability factor and new treatment target for stimulant addiction (2013) Front Psychiatry 23; 4:109).
In recent decades, development of new treatments for psychostimulant addiction has been a major focus of multidisciplinary research efforts, and has included molecular approaches, preclinical behavioural studies, and clinical trials.
Soria and colleagues observed that CB1 receptor deletion impairs the acquisition of cocaine self-administration by mice, and both genetic and pharmacological CB1 receptor blockade reduces the motivation for cocaine under a progressive ratio schedule of reinforcement (Soria et al., Lack of CB1 cannabinoid receptor impairs cocaine self-administration (2005) Neuropsychopharmacology 30:1670-1680).
The CB1 receptor antagonist AM251 significantly attenuates the motivation for cocaine self-administration under a progressive ratio schedule of reinforcement (Xi et al., Cannabinoid CB1 receptor antagonists attenuate cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats (2008) Neuropsychopharmacology 33(7), 1735-1745), reduces methamphetamine self-administration (Vinklerova et al., Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251 (2002). J Psychopharmacol 16:139-143) and attenuates cocaine-induced enhancement in the sensitivity to brain stimulation reward (Xi et al., Cannabinoid CB1 receptor antagonists attenuate cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats (2008, Neuropsychopharmacology 33(7), 1735-1745).
Orio and colleagues found that the CB1 receptor influence on cocaine reward is enhanced by long periods of cocaine self-administration that result in progressive increases in cocaine intake (Orio et al., A role for the endocannabinoid system in the increased motivation for cocaine in extended-access conditions (2009) J Neurosci 29(15), 4846-4857). These observations show that neuroadaptations induced by extended cocaine exposure may recruit a CB1 receptor involvement in a progressive escalation of drug intake that results from extended periods of cocaine use.
Thus the targeted administration of selective CB1 receptor antagonists, according to the present invention, are useful in the alleviation of chemical dependency associated with, and withdrawal from, psychostimulants.
Alcohol Addiction
Alcohol is possibly the habit-forming drug that has recently been more studied for its relationships with the endocannabinoid signaling system (Hungund and Basavaraj appa, Are anandamide and cannabinoid receptors involved in ethanol tolerance? A review of the evidence (2000) Alcohol., 35:126-133.) This can be concluded from genetic studies that have proved a greater frequency for the appearance of a genetic polymorphism for the cannabinoid CB1 receptor in several subpopulations of alcoholic patients, in particular in alcoholics with severe withdrawal signs, such as delirium or seizures (Schmidt et al., Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence (2002) Drug Alcohol Depend., 65, 221-224), or with antecedents of childhood attention deficit/hyperactivity (Ponce et al., Association between cannabinoid receptor gene (CNR1) and childhood attention deficit/hyperactivity disorder in Spanish male alcoholic patients (2003) Mol. Psychiatry, 8, 466-467), and also from biochemical studies that examined the effects of alcohol exposure on endocannabinoid signaling in laboratory animals or cultured nerve cells (Basavarajappa et al., Chronic ethanol administration down-regulates cannabinoid receptors in mouse brain synaptic plasma membrane (1998) Brain Res., 79, 212-218).
Chronic alcohol exposure modifies endocannabinoid levels in different brain regions, while pharmacological targeting of the endocannabinoid system has been reported to influence ethanol intake in laboratory animals. Pharmacological targeting of this system serves to reduce the incentive properties of alcohol, the signs of alcohol withdrawal, and/or the vulnerability to relapse. Mice treated with CB1 antagonists showed a significant reduction in self-administered alcohol consumption (Colombo et al., Suppressing effect of the cannabinoid CB1 receptor antagonist, SR 141716, on alcohol's motivational properties in alcohol-preferring rats (2004) Eur J Pharmacol 498: 119-123).
The instant invention provides for the administration of unique dosage forms of cannabinoids, including CB1 receptor antagonists like SR 141716 and other CBD antagonists, in the treatment of alcohol dependence.
Nicotine Addiction
CB1 knockout mice indicate a critical role of CB1 receptors in the rewarding effects of nicotine (Valjent et al., Behavioural and biochemical evidence for interactions between Delta 9-tetrahydrocannabinol and nicotine (2002) Br J Pharmacol 135(2), 564-578). Similarly, the administration of CB1 receptor antagonists like SR141716A have been successful in blocking the acquisition of nicotine-induced conditioned place preference in rats (Le Foll and Goldberg, Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place preferences (2004) Neuroreport 15(13), 2139-2143; Forget et al., Cannabinoid CB1 receptors are involved in motivational effects of nicotine in rats (2005). Psychopharmacology (Berl) 181(4), 722-734); Cohen et al., SR141716, a central cannabinoid (CB1) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats (2002) Behav Pharmacol 13: 451-463).
Cannabinoid CB1 receptors are involved in motivational effects of nicotine in rats (2005) Psychopharmacology (Berl) 181(4), 722-734). Along with the more selective CB1 antagonist AM251, SR14176A dose-dependently reduces nicotine self-administration by rats (Cohen et al., SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats (2002) Behav Pharmacol 13: 451-463).
The instant invention provides a measured dosage form capable of predictably administering precise, therapeutically effective amounts of cannabinoids, including, but not limited to, CB1 receptor antagonists as a means of reducing nicotine dependency.
Treatment of Adverse Effects Associated with Dependency and Withdrawal
High CBD intake relative to THC has been associated with lower scores on the positive dimensions of the CAPE (Community Assessment of Psychic Experiences) Scale, inhibition of psychotic symptoms, and reduced deficiencies in episodic memory (Englund et al., Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Pharmacol (2013) 27(1): 19-27). The present formulations present the advantage of an intentional dosage of synthetic or natural preparations with ideal pharmacology, to the exclusion of other cannabinoids, if desired, and their respective pharmacokinetic and pharmacodynamics influences. The “protective effects” afforded by extended or sustained release formulations can be harnessed by virtue of the present invention, along with the desired therapeutic effects of cannabidiols, either alone or in concert with therapeutically effective amounts of other cannabinoids.
The endocannabinoid system is intricately involved in the pathophysiology of depression, with CB1 receptors widely distributed in brain areas related to affective disorders, where expression is otherwise regulated by anti-depressants (Devane et al., Determination and characterization of a cannabinoid receptor in rat brain, Mol Pharmacol (1988) 34: 605-613; Hill and Gorzalka, Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression?Behav Pharmacol (2005) 16: 333-352; Hill et al., Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment, J Neurochem (2008) 106: 2322-36).
Administration of CBD achieves characteristic effects of induced anti-psychotic and anxiolytic activity in subjects, and also attenuates the development of stress-induced behavioural consequences (Guimaraes et al., Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (1990) 100: 558-559; Resstel et al., Effects of cannabidiol and diazepam on behavioural and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res (2006) 172(2): 294-98; Resstel et al., 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol (2009) 156(1): 181-88; Zuardi et al., Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (1982) 76: 245-50).
The instant invention is important and useful because CBD has a favorable profile in a model predictive of antidepressant-like activity in comparison to antidepressants, but such effects are only attainable at precise dosages, with smaller or higher doses producing no effect (Porsolt et al., Depression: a new animal model sensitive to antidepressant treatment. Nature (1977) 266:730-32; Zanelati et al., Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol (2010) 159:122-28). The present invention provides formulations which are capable of administering dosages in accordance with the most clinically appropriate pharmacokinetic and pharmacodynamic profile in order to achieve desired therapeutic effects in a patient presenting with a specific pathophysiology, such as major depressive disorder.
Sleep disturbances are a common adverse effect associated with withdrawal from chemical dependency, and for which certain cannabinoids can provide relief. The chemistry of CBD has been examined, and its central nervous system (CNS) pharmacological properties, including its anticonvulsant, anxiolytic, and sedative effects, have been documented (Chesher et al., (1975) Interaction of D9-tetrahydrocannabinol and cannabidiol with phenobarbitone in protecting mice from electrically induced convulsions. J. Pharm. Pharmacol. 27:608-609; Pickens, (1981). Sedative activity of Cannabis in relation to its delta′-trans-tetrahydrocannabinol and cannabidiol content. Br. J. Pharmacol. 72:649-656; Russo and Guy, (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med. Hypotheses 66:234-246).
It has been shown that CBD improves sleep in individuals suffering from insomnia (Carlini and Cunha, Hypnotic and antiepileptic effects of cannabidiol. J. Clin. Pharmacol. 21 (suppl 8-9), 417S-427S). It has been successfully employed to block anxiety-induced REM sleep alteration via its anxiolytic effects (Hsiao et al., Effect of cannabidiol on sleep disruption induced by the repeated combination tests consisting of open field and elevated plus-maze in rats. Neuropharmacol (2012) 62: 373-84). Other studies have exhibited clinically significant improvements in sleep in subjects suffering from post-traumatic stress-related insomnia, even when subjects received no pharmaceutical medications to treat sleep disorders aside from cannabidiol oil (Shannon, Effectiveness of cannabidiol oil for pediatric anxiety and insomnia as part of posttraumatic stress disorder: a case report. Perm J (2016) 20(4): 16-005). The systemic acute administration of CBD increases total sleep time in subjects, in addition to increasing sleep latency in the light period of the day of administration (Chagas et al., Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats. J. Psychopharmacol (2013) 27:312-16).
Treatment of Drug-Seeking (Relapse)
Both positive and negative memories and conditioned cues associated with drug use perpetuate drug-seeking behaviour and the continued cycle of abuse.
Drug exposure produces powerful interoceptive effects that become associated with environmental cues, such that these cues alone can induce craving and promote relapse following periods of abstinence (Carter and Tiffany, Cue-reactivity and the future of addiction research (1999) Addiction 94: 349-51). In addition to conditioned drug memories, acute exposure to a preferred drug or pharmacologically related agent (that is, drug priming) and stressful events can precipitate relapse (Koob and Kreek, Stress, dysregulation of drug reward pathways, and the transition to drug dependence (2007) Am J Psychiatry 164: 1149-1159).
Animal models of relapse demonstrate an important cannabinoid influence on the reinstatement of extinguished drug-seeking and drug-taking behaviours. Cannabinoid CB1 receptors control conditioned drug seeking. Trends Pharmacol. Sci. 26, 420-426. CB1R blockade attenuates relapse-like behaviour in rats, thus paving the way for numerous studies demonstrating a potent influence of CB1R signalling on relapse-like behaviour induced both by drug exposure and by drug-paired conditioned cues across multiple classes of abused drugs (Fattore et al., An endocannabinoid mechanism in relapse to drug seeking: a review of animal studies and clinical perspectives (2007). Brain Res. Rev. 53, 1-16.)
CB1R antagonism attenuates drug-primed, cue-induced and some forms of stress-induced reinstatement of cocaine- and methamphetamine-seeking behaviour in rats (Serrano and Parsons, (2011). Endocannabinoid influence in drug reinforcement, dependence and addiction-related behaviors. Pharmacol. Ther. 132, 215-241.)
Thus, CB1R signalling modulates drug-seeking for various pharmacologically distinct drugs. There is also evidence that CB1R antagonism blocks both cue- and priming-induced reinstatement of seeking behaviour for non-drug rewards, such as sucrose and corn oil (De Vries et al., (2005), Suppression of conditioned nicotine and sucrose seeking by the cannabinoid-1 receptor antagonist SR141716A. Behav. Brain Res. 161, 164-168.
Cannabinoid Pharmacokinetics
Dronabinol has been approved by the Food and Drug Administration for the control of nausea and vomiting associated with chemotherapy, as well as for appetite stimulation in patients suffering from wasting syndrome. While synthetic dronabinol is a recognized pharmaceutically active ingredient, natural botanic sources of THC are also known in the art. Any or all of these cannabinoids may be used in the present invention.
Marinol® is manufactured as a gelatin capsule containing dronabinol in a suspension of sesame oil. It is taken orally, and is available in round, soft gelatin capsules containing either 2.5 mg, 5 mg, or 10 mg dosages of dronabinol. It is presently prescribed for the treatment of cachexia in patients with AIDS, and for the treatment of nausea and vomiting associated with chemotherapy in cancer patients who have failed to respond to conventional antiemetic treatments. Like other oils provided in gelatin dosage forms, there is an urgent need for solid (powder and tablet) unique and controlled-release dosage forms of this drug, as provided in the instant invention.
Despite FDA approval, it is almost universally accepted that medical marijuana possesses many benefits over the synthesized dronabinol found in Marinol, and that, by prohibiting the possession and use of natural Cannabis and its myriad cannabinoids, patients are unnecessarily restricted to use of a synthetic substitute lacking the robust therapeutic efficacy of its natural analog. Anecdotal reports indicate that patients prescribed Marinol® report adverse psychoactive effects with greater frequency, lasting 4-6 hours, as well as drowsiness, dizziness, confusion, anxiety, impairment, and depression (Why Marinol® is not as good as marijuana, supra).
Cannabis sativa, in its crude form, often also possesses cannabinoids with undesirable effects in subjects, such as prolonged psychoactive effects. The present invention seeks to manipulate those properties and the pharmacokinetic profiles of the various cannabinoids within a novel drug delivery system in order to yield desired therapeutic effects in subjects over specific periods of time, while minimizing adverse effects.
Sativex® is another cannabinoid-based drug that is an improvement over Marinol® in certain aspects. It is an oral Cannabis spray consisting of natural cannabinoid extracts. It possesses greater bioavailability and uptake upon interaction with the subject's endocannabinoid receptors, and has a consequently reduced time for onset of action relative to that of the synthetic dronabinol in Marinol®.
In this aspect, it is a superior cannabinoid drug to Marinol®—but oral sprays are plagued by their own shortcomings, including long tmax values ranging from 1 to 4 h for Marinol® and 3.3 to 4.0 h for Sativex® (Davis M P. Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain. Expert Opin Investig Drugs. (2008) 17:85-95; Karschner E L, Darwin W D, Goodwin R S, Wright S, Huestis M A. Plasma cannabinoid pharmacokinetics following controlled oral {Delta}9-Tetrahydrocannabinol and oromucosal Cannabis extract administration. Clin Chem. (2011) 57:66-75). Long times to reach maximal concentration can present a disadvantage for on-demand symptomatic treatment.
The alternative of existing gelatin-capsule formulations of Marinol® present their own challenges, as their variable pharmacokinetics result in significant variations in peak plasma concentrations (150-200%) (Naef M, Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden A, Brenneisen R. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain. (2003) 105:79-88; Wall M E, Perez-Reyes M. The metabolism of delta 9-tetrahydrocannabinol and related cannabinoids in man. J Clin Pharmacol. (1981) 21:178S-89S; see also Why Marinol® is Not as Good as Real Marijuana, posted by Johnny Green on Mar. 5, 2012, www.theweedblog.com/why-marinol-is-not-as-good-as-real-marijuana, incorporated in its entirety accessed Mar. 5, 2017). This is unfavourable for accurate dose regulation. As a result of these shortcomings, Sativex® and Marinol® have not been widely adopted as a replacement for medical marijuana.
Further, Marinol® lacks several of the therapeutic benefits of other cannabinoids present in Cannabis sativa, of which there are more than 66. Synthetic dronabinol, the active ingredient in Marinol®, is itself a derivative or analog of one such compound (delta-9-tetrahydrocannabinol or THC). But importantly, several other cannabinoids in Cannabis sativa, in addition to naturally occurring terpenoids (oils) and flavonoids (phenols), have been clinically demonstrated to possess therapeutic utility. The presence of these myriad other therapeutically effective cannabinoids factors largely into patients' persistent preference for natural Cannabis. 
One such cannabinoid is CBD, which, as set out above, has clinically demonstrated anxiolytic, analgesic, anti-psychotic, anti-epileptic, anti-spasmodic, and anti-rheumatoid arthritic properties. Natural CBD extracts, when administered in conjunction with natural or synthetic THC, are also capable of inhibiting undesirable effects of THC, such as its induction of anxiogenic, psychotic, and psychoactive activity in patients. Along with these inhibitory effects, CBD, administered with THC, has resulted in clinically significant reductions in pain, spasticity, and other symptoms in multiple sclerosis (MS) patients non-responsive to existing treatment options; this is particularly the case with severe or advanced-stage MS.
CBD has been shown to be neuroprotective against glutamate neurotoxicity (i.e., stroke); cerebral infarction (localized cell death in the brain); and ethanol-induced neurotoxicity, with CBD exhibiting greater protective properties than either ascorbate (vitamin C) or alpha-tocopherol (vitamin E). Clinical trials have shown CBD to possess anti-tumoral properties, inhibiting the growth of glioma (brain tumor) cells in a dose-dependent manner, and selectively inducing apoptosis (programmed cell death) in malignant cells, a significant clinical advantage. Dosage formulations of CBD and other cannabinoids can also be formulated into solid dosage forms according to the present invention.
Additional cannabinoids possessing clinically demonstrated therapeutic properties include: cannabinol (anti-convulsant and anti-inflammatory activity); cannabichromine (anti-inflammatory and anti-depressant activity); and cannabigerol (anti-tumoral and analgesic activity). The essential oil components (terpenoids) of Cannabis sativa exhibit anti-inflammatory properties, and its flavonoids express antioxidant activity.
Emerging clinical evidence suggests that cannabinoids may act to slow disease progression in certain autoimmune and neurologic diseases, including MS, amyotrophic lateral sclerosis (Lou Gehrig's disease), and Huntington's disease. (Johnny Green, supra). Dosage formulations of these cannabinoids can be formulated into solid dosage forms in accordance with the present invention.
Oral ingestion of Marinol® sidesteps the potential side effects of smoking, but because of the poor bioavailability of its constituent dronabinol, only 5-20% of orally-administered THC reaches the blood stream, and the drug may not attain peak effect until more than 4 hours after administration. (National Academy of Sciences, Institute of Medicine. Marijuana and Medicine: Assessing the Science Base. (1999) p. 203; Growing L., et al. Therapeutic use of Cannabis: clarifying the debate. Drug and Alcohol Review (1998)). Moreover, because dronabinol is metabolized slowly, its therapeutic and psychoactive effects may be unpredictable and vary considerably, both from one person to another, and in the same person, from one episode of use to another (Calhoun S., et al. Abuse potential of dronabinol. Journal of Psychoactive Drugs (1998) 30: 187-196; Morgan J., Zimmer L. Marijuana myths, marijuana facts: A review of the scientific evidence. P. 19). Thus, there is a need for improved bioavailability dosage forms of both natural and synthetic cannabinoids with more precise pharmacokinetics.
As a result of Marinol's® slow onset and poor bioavailability, scientists are developing a new formulation of pulmonary dronabinol, delivered with a pressurized metered dose inhaler (Medical News Today. New synthetic delta-9-THC inhaler offers safe, rapid delivery, phase I study. Apr. 17, 2005). Unlike oral synthetic THC, it's possible that pulmonary Marinol® (and by inference, its active ingredient, dronabinol) “could offer an alternative for patients when a fast onset of action is desirable”, a significant improvement over onset times ranging from 1-4 h.
U.S. Pat. No. 6,403,126 (incorporated herein by reference in its entirety) discloses methods of extracting and purifying cannabinoids from Cannabis using organic solvent.
An analog of dronabinol, nabilone, is also available commercially.
US 20120231083 discloses a sustained release medicament, which results in delivery of a therapeutic level of one or more cannabinoids during a clinically relevant therapeutic window. The therapeutic window is a longer window than provided by an fast or even immediate release medicament such as Marinol®, containing an equivalent amount of the cannabinoid.
In contrast, oral administration of the present compositions provide therapeutic dosing while maintaining safe, side effect-sparing levels of cannabinoid. They also provide methods of precisely modulating the administration of the cannabinoids, and thereby treating patients with cannabinoid-sensitive disorders.
US 20060257463 discloses a method of transmucosally delivering a cannabinoid to a subject in need of treatment, comprising the steps of: administering to the subject a transmucosal preparation containing the cannabinoid wherein said transmucosal preparation is made by incorporating an effective amount of the cannabinoid via hot-melt extrusion technology, hot-melt molding, admixing, or a solvent cast technique into a film matrix or a reservoir containing the cannabinoid, and attaching said transmucosal preparation to the mucosa of the subject.
Pharmaceutical compositions comprising the cannabinoid active pharmaceutical ingredient, crystalline trans-(±)-delta9-tetrahydrocannabinol, and formulations thereof, are disclosed in WO 2006133941. The invention also relates to methods for treating or preventing a condition, such as pain, comprising the administration to a patient in need thereof an effective amount of crystalline trans-(±)-delta9-tetrahydrocannabinol. In specific embodiments, the crystalline trans-(±)-delta9-tetrahydrocannabinol can be administered according to the methods for treating or preventing a condition such as pain, and can have a purity of at least about 98% based on the total weight of the cannabinoids.
US 2003/0229027 discloses oral cannabinoid formulations involving encapsulating the cannabinoids with sugar and sugar alcohols.
US 2005/0090468 discloses complexes of cannabinoids with methylated cyclodextrins.
US 2007/0104741 discloses a self-emulsifying drug delivery system alleged to improve dissolution, stability, and bioavailability of drug compounds of dronabinol or other cannabinoids.
US 20140100269 discloses oral cannabinoid formulations, including an aqueous-based oral donabinol solution, that are alleged to be stable at room or refrigerated temperatures.
U.S. Pat. No. 8,632,825 discloses the use of a combination of cannabinoids, particularly tetrahydrocannabinol (THC) and cannabidiol (CBD), in the manufacture of a medicament for use in the treatment of cancer.
U.S. Pat. No. 6,630,507 discloses that cannabinoids have antioxidant properties. This property makes them useful in the treatment and prophylaxis of a wide variety of oxidation-associated diseases, such as ischemic, age-related, inflammatory, and autoimmune diseases. The cannabinoids are found to have particular application as neuroprotectants, for example, in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Non-psychoactive cannabinoids, such as cannabidiol, are particularly advantageous to use because they avoid toxicity that is encountered with psychoactive cannabinoids at high doses, useful in the present invention.
U.S. Pat. No. 8,808,734 discloses liposomal and micelle formulations of cannabinoid analogues. U.S. 67/475,058 discloses composition for inhalation therapy comprising delta-9-tetrahydrocannabinol and semi-aqueous solvents.
Dosage and Administration of Dronabinol from FDA Document NDA 18-651/S-021; 500012 Rev September 2004:                Appetite Stimulation: Initially, 2.5 mg dronabinol capsules should be administered orally twice daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or bedtime. If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day, administered in divided oral doses. Caution should be exercised in escalating the dosage because of the increased frequency of dose-related adverse experiences at higher dosages.        Antiemetic: Best administered at an initial dose of 5 mg/m2, given 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15 mg/m2 dose. Caution should be exercised in dose escalation, however, as the incidence of disturbing symptoms increases significantly at maximum dose.        
Despite all of the work on new dosage formulations of cannabinoids and dronabinol, there is a need in the art for simple, inexpensive, improved dosage forms that have an improved profile with faster onset, extended release profiles, and lower inter-subject variability than currently available cannabinoid products.
In the 1970s and 1980s, there were almost no marketed drugs with less than 10 μg/ml solubility (10-100 μg/ml was considered low) (Solid Dispersions: New Approaches and Technologies in Drug Delivery, Controlled Release Society; Rutgers, N.J., 2 Jun. 2009, Craig A. McKelvey, Merck & Co., Inc., hereinafter “McKelvey”). Presently, it is estimated that more than 60% of active pharmaceutical ingredients (APIs) in development have poor bioavailability due to low aqueous solubility (WO 2013040187, citing Manufacturing Chemist, March 2010, 24-25). At least partially as a result of advances in combinatorial chemistry and molecular screening methods for identifying potential drug candidates, an increasing number of insoluble drugs are being identified. Formulation methods are also evolving in an attempt to keep up but formulation and expense are often problematic.
Poor solubility of compounds may result in ineffective absorption, which is an important part of the high clinical failure rate due to poor pharmacokinetics. Drugs with very low aqueous solubility often have sizeable within- and between-subject pharmacokinetic variability, making study design and the conduct of clinical studies very challenging, the assessment of dose-response and exposure-response relationships difficult, and resulting in difficult dose determination. Water insoluble drugs often have high propensity for drug interactions at the absorption level, such as food interactions, and interactions with gastrointestinal “GI” pro-kinetic agents, especially if these drugs also have narrow therapeutic windows. There is an on-going need in the art for better formulation technologies for poorly soluble drugs (Jain et al., Asian J Pharm Clin Res, Vol 5, Suppl 4, 2012, 15-19).
A drug substance is generally considered highly soluble when the highest dose strength is soluble in 250 ml water over a pH range of 1 to 7.5. A drug is generally considered highly permeable when the extent of absorption in humans is determined to be 90% of an administered dose, based on the mass balance or in comparison to an intravenous dose (drug and metabolite). A drug product is generally considered to dissolve rapidly when 85% of the labeled amount of substance dissolves within 30 minutes, using USP apparatus I or II in a volume of 900 ml buffer solution. (Gothoskar A. V. Biopharmaceutical classification of drugs. Pharm Rev. 2005; 3:1.).
For BCS Class II drugs that have low bioavailability resulting from poor solubility and the inability to dissolve rapidly the selection of formulation is often a major hurdle preventing the development of a successful oral drug product. Certain technologies have recently been developed to aid in the formulation of these drugs including: salt formation, size reduction, co-solvency, pH manipulation, surfactant and micelle use, inclusion complexes, lipid formulations, and solid dispersions. Jain et al. Asian J Pharm Clin Res, Vol 5, Suppl 4, 2012, 15-19).
According to the “Intra-Agency Agreement Between the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the U.S. Food and Drug Administration (FDA) Oral Formulations Platform-Report 1” dronabinol is a class 2 or class 4 drug with low solubility and unknown permeability. Thus it may be formulated in the same manner as a class 2 drug.
Absorption and distribution: Dronabinol capsules are almost completely absorbed (90 to 95%) after single oral doses. Due at least in part to the effects of first pass hepatic metabolism only 10 to 20% of the administered dose reaches the systemic circulation (FDA document NDA 18-651/S-021).
The advantages of controlled release products are well known in the pharmaceutical field. Controlled release drug formulations may be useful to reduce the frequency of drug administration (especially in the case of drugs with short compound half lives), improve patient adherence, reduce drug toxicity (local or systemic associated with high peak exposure), reduce drug level fluctuation in blood, stabilize medical condition with more uniform drug levels, reduce drug accumulation with chronic therapy, improve bioavailability of some drugs because of spatial control, and reduce total drug usage when compared with fast or even immediate release drugs.
Oral controlled release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and temporal requirements.
Mechanical devices aside, interaction between a drug and a polymeric material often forms the basis of controlled oral drug delivery. A polymer at certain concentrations in a solution imposes pathways for drug diffusion. Polymers that dissolve in or otherwise hydrate in aqueous media can alter the drug diffusion process in a time-dependent manner. For example, a commonly used material, hydroxypropyl methylcellulose (HPMC), which is water soluble, behaves as a swellable absorptive polymer in the limited volumes of aqueous media in the gastrointestinal tract. Drug dispersed in this polymer, as in monolithic tablets, diffuses through the viscous hydrated polymer at a rate dependent on the movement kinetics of the polymer chains. The faster these relax, the faster the diffusion rate.
Development of dosage form depends on chemical nature of the drug and polymers, the matrix structure, swelling, diffusion, erosion, the release mechanism and the in vivo environment.
Hydrophilic polymers like HPMC may also control drug release by erosion mechanisms. After consumption of the dosage form, the GI tract fluid encounters the dosage unit, causing the polymer to hydrate and swell. Weakened mechanical properties in the swollen state may cause the hydrated polymer to break away from the prime particle (compact or pellet). Drug release may therefore be controlled by a combination of diffusion and erosion. Such release mechanisms can apply to systems where drug is dispersed in or coated with polymer.
Extended release dosage forms of class 2 drugs often require expensive, difficult, and proprietary osmotic delivery systems such as Alza's Oros™ and Duros™ technologies. (See U.S. Pat. Nos. 4,612,008; 4,327,725; 4,765,989; and 4,783,337). Other technologies have been developed to exploit diffusion, erosion, and other physicochemical mechanisms and provide drug and disease-specific release profiles. Examples also include the release from a Contramid™ tablet controlled by the degree of crosslinking of high amylase starch.
Simple extended release formulations include the use of water insoluble polymers which can be used in coating-based extended drug release formulations. These include methacrylate- or acrylate-based polymers with low permeability.
Hydrophilic functional groups such as trimethylaminoethyl methacrylate can improve permeability and swellability in water, thus altering release behaviors.
Various drug candidates such as diltiazem hcl, carbamazepine, metoprolol, oxprenolol, nifedipine, glipizide have been formulated as osmotic delivery systems. Problems with such osmotic delivery systems include the need for special equipment for making an orifice in the system; residence time of the system in the body varies with the gastric motility and food intake; such systems may cause irritation or ulcer due to release of saturated solutions of drug. Online Available at www.thepharmajournal.com. THE PHARMA INNOVATION Vol. 1 No. 7 2012 “www.thepharmajournal.com” Page|116 Osmotic-Controlled Release Oral Delivery System: An Advanced Oral Delivery Form. Nitika Ahuja, Vikash Kumar, Permender Rathee. Accessed Mar. 5, 2017.
The instant invention solves many problems associated with current delivery of cannabinoids and provides for both cannabinoid immediate and sustained release dosage forms in a technically and economically efficient and surprising manner.
In general, the most desirable oral dosage form is a tablet, and it would be advantageous if a cannabinoid containing tablet could be made available which does not suffer from the obstacles of prohibitively expensive drug delivery systems, nor the need for smoking or “edible” dosage forms. None of the documents described above enable controlled release cannabinoid tablets that combine the requirements for instant relief with long lasting effects. There is a need for new cheap and stable dosage formulations, especially tablets, comprising multiple effective dose of cannabinoids or derivatives thereof. There is also a need for a stable cannabinoid powder.
Another aspect the invention provides a pharmaceutical or nutraceutical composition in the form of a tablet for oral administration comprising cannabinoid wherein said tablet is preferably formed from a pharmaceutically or even nutraceutically acceptable powder.
By “nutraceutical” is meant a composition that provides medical or health benefits, including the prevention and treatment of disease. Dietary supplements and natural health products are examples of nutraceuticals. In many places natural cannabinoids are considered nutraceuticals. Within the context of this invention it is understood that the term “drug” is used generically to include prescription and non-prescription pharmaceutical products as well as nutraceuticals including dietary supplements, natural health products, medicinal foods, drinks, candy bars with active ingredients and all other similar delivery methods whether approved or unapproved.
Viewed from another aspect the invention provides a pharmaceutical or nutraceutical tablet as hereinbefore described for use in the treatment or prophylaxis of all of the disorders that medical marijuana and drabinol is used for at the present time.
As used herein, the term “drug” includes not only FDA approved pharmaceuticals but also natural medicines, alternative medicines, and dietary supplements and generally refers to all forms of cannabinoids.